Carbon-to-nitrogen atom swap enables direct access to benzimidazoles from drug-like indoles
Ann-Sophie K. Paschke, Yannick Brägger, Bence B. Botlik, Erich Staudinger, Ori Green, Bill Morandi
Abstract
The ability to selectively edit organic molecules at the atomic level has the potential to streamline lead discovery and optimization in the pharmaceutical and agrochemical industry. While numerous atom insertion and deletion reactions have recently been reported, examples of single atom swaps remain scarce due to the challenge of orchestrating the selective cleavage and formation of multiple chemical bonds around the same atom. Here we report a method for the carbon-to-nitrogen atom swap in N-alkyl indoles, allowing the direct conversion of indoles to the corresponding benzimidazoles. The reaction leverages the innate reactivity of the indole scaffold to engage in an initial oxidative cleavage step, followed by oxidative amidation, Hofmann-type rearrangement and cyclization. This complex sequence of steps is mediated by the simple combination of commercially available phenyliodine(III) diacetate and ammonium carbamate as the nitrogen atom source. The reaction tolerates a wide range of functional groups, which is demonstrated by the interconversion of 15 drug-like molecules, implying its immediate applicability across a wide range of discovery programmes.